Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

Obesity, insulin resistance and their attendant complications are among the leading causes of morbidity and premature mortality today, yet we are only in the early stages of understanding the molecular pathogenesis of these aberrant phenotypes. A powerful approach has been the study of rare patients with monogenic syndromes that manifest as extreme phenotypes. For example, there are striking similarities between the biochemical and clinical profiles of individuals with excess fat (obesity) and those with an abnormal paucity of fat (lipodystrophy), including severe insulin resistance, dyslipidaemia, hepatic steatosis and features of hyperandrogenism. Rare lipodystrophy patients therefore provide a tractable genetically defined model for the study of a prevalent human disease phenotype. Indeed, as we review herein, detailed study of these syndromes is beginning to yield valuable insights into the molecular genetics underlying different forms of lipodystrophy, the essential components of normal adipose tissue development and the mechanisms by which disturbances in adipose tissue function can lead to almost all the features of the metabolic syndrome.

Background: Iron repletion augments exercise capacity in chronic heart failure (HF), but there is a lack of mechanistic data explaining how iron could augment exercise performance despite minimal changes in hemoglobin (Hb). Besides Hb, iron is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine (PCr). Dynamic phosphorus magnetic resonance spectroscopy is a noninvasive tool that quantifies in vivo muscle energetics by measuring the kinetics of PCr recovery after exertion. We tested the hypothesis that intravenous iron repletion in chronic HF enhances skeletal muscle energetics as reflected by shorter PCr recovery half-times (PCr t 1/2 ) on phosphorus magnetic resonance spectroscopy. Methods: We enrolled 40 patients (50% anemic) with chronic HF, New York Heart Association class ≥II, left ventricular ejection fraction ≤45%, and iron deficiency (ferritin<100 μg/L or 100–300 μg/L with transferrin saturation <20%). Subjects underwent stratified (anemic versus nonanemic) randomization (1:1) to a single, double-blinded, total dose infusion of iron isomaltoside or saline placebo with end points reassessed early at 2 weeks posttreatment to minimize confounding from exercise adaptation. The primary end point was PCr t 1/2 at 2 weeks. Secondary end points included ADP recovery half-time (ADP t 1/2; energetic marker), iron status, symptoms, Hb, exercise capacity, and safety. Results: In the total population, treatment groups were similar at baseline. At 2 weeks, iron isomaltoside improved PCr t 1/2 (adjusted difference, –6.8 s; 95% CI, 11.5 to –2.1; P =0.006), ADP t 1/2 (–5.3 s; 95% CI, –9.7 to –0.9; P =0.02), ferritin (304 ng/mL; 95% CI, 217–391; P <0.0001), transferrin saturation (6.8%; 95% CI, 2.7–10.8; P =0.002), New York Heart Association class (–0.23; 95% CI, –0.46 to –0.01; P =0.04), resting respiratory rate (–0.7 breaths/min; 95% CI, –1.2 to –0.2; P =0.009), and postexercise Borg dyspnea score (–2.0; 95% CI, –3.7 to –0.3; P =0.04), but not Hb (2.4 g/L; 95% CI, –3.5 to 8.4; P =0.41). Adverse events were similar between groups. In subgroup analyses, iron isomaltoside improved PCr t 1/2 in anemic (–8.4 s; 95% CI, –16.7 to –0.2; P =0.04) and nonanemic (–5.2 s; 95% CI, –10.6 to 0.2; P =0.06) cohorts. Conclusions: In patients with chronic HF and iron deficiency, a total repletion dose of iron isomaltoside given at a single sitting is well tolerated and associated with faster skeletal muscle PCr t 1/2 at 2 weeks, implying better mitochondrial function. Augmented skeletal muscle energetics might therefore be an important mechanism via which iron repletion confers benefits in chronic HF despite minimal Hb changes. Clinical Trial Registration: URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005592-13/GB . Unique identifier: EudraCT 2012-005592-13.

Accurate measures of visceral and abdominal subcutaneous fat are essential for investigating the pathophysiology of obesity. Classical anthropometric measures such as waist and hip circumference cannot distinguish between these two fat depots. Direct imaging methods such as computed tomography and magnetic resonance imaging (MRI) are restricted in large‐scale studies due to practical and ethical issues. We aimed to establish whether ultrasound is a valid alternative method to MRI for the quantitative assessment of abdominal fat depots in older individuals. The study population comprised 74 white individuals (41 men and 33 women, aged 67–76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial. Anthropometry included height, weight, waist and hip circumferences. Abdominal fat was measured by ultrasound in two compartments: visceral fat defined as the depth from the peritoneum to the lumbar spine; and subcutaneous fat defined as the depth from the skin to the abdominal muscles and compared to reference measures by MRI (10‐mm single‐slice image). Ultrasound measures were positively correlated with MRI measures of visceral and subcutaneous fat (visceral: r = 0.82 and r = 0.80 in men and women, respectively; subcutaneous: r = 0.63 and 0.68 in men and women, respectively). In multiple regression models, the addition of ultrasound measures significantly improved the prediction of visceral fat and subcutaneous fat in both men and women over and above the contribution of standard anthropometric variables. In conclusion, ultrasound is a valid method to estimate visceral fat in epidemiological studies of older men and women when MRI and computed tomography are not feasible.